Ibrutinib Benefits R/R CLL, but Combo Therapy Works Better

Ibrutinib remains a key treatment for relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), but combining it with other therapies can significantly enhance patient outcomes, according to new research.¹

A meta-analysis published in BMC Pharmacology and Toxicology included data from 21 clinical studies and, according to the study authors, reinforces ibrutinib’s effectiveness and sheds light on optimal treatment strategies in the CLL space.

BTK inhibitor ibrutinib has emerged as a targeted therapy that disrupts malignant B-cell proliferation. | Image credit: CLShebley – stock.adobe.com

Researchers found that single-agent ibrutinib achieved a complete response (CR) rate of 9% and an overall response rate (ORR) of 77%, but the combination therapy yielded even better outcomes. When used with other agents, ibrutinib improved the CR rate to 21% and the ORR to 84%, demonstrating the benefits of multiagent approaches in treating relapsed CLL.

The researchers also observed that adverse events did not significantly impact treatment success. However, toxicity did lead to treatment modifications in some cases, with 16% to 24% of patients discontinuing ibrutinib due to intolerance and 13% to 23% requiring dose adjustments.

“Evaluating ibrutinib’s adverse effects revealed varying trends in grade 3 and 4 events while highlighting consistent neutropenia, anemia, and thrombocytopenia patterns,” the authors wrote. “Nevertheless, the differences in results and the heterogeneity in comparisons with other medications or combinations emphasize the need for additional research to improve treatment methods for patients with R/R CLL, focusing on both effectiveness and adverse effects.”

Ibrutinib’s Role in CLL Treatment

CLL is a slow-growing B-cell malignancy that primarily affects older adults.² Although chemoimmunotherapy has been a traditional treatment, many patients exhibit resistance or are ineligible due to age and comorbidities.¹ Ibrutinib, a Bruton tyrosine kinase (BTK) inhibitor, has emerged as a targeted therapy that disrupts malignant B-cell proliferation.

Other researchers are also looking into how to combine ibrutinib with other treatments to boost outcomes. One recent study suggested combining ibrutinib with venetoclax and using measurable residual disease (MRD) to guide treatment decisions could further optimize patient outcomes.³ The phase 3 FLAIR trial (ISRCTN01844152) demonstrated that MRD-driven ibrutinib-venetoclax therapy significantly improved progression-free survival compared with standard chemoimmunotherapy. Additionally, MRD monitoring allowed many patients to discontinue treatment early, reducing unnecessary exposure to therapy and potential toxicity.

Although the combination of ibrutinib and venetoclax showed strong efficacy, the FLAIR trial also highlighted the need for careful management of adverse events, particularly cardiac complications. These findings align with the meta-analysis' conclusion that combination therapy enhances treatment responses, reinforcing the importance of ongoing research into multiagent regimens and personalized treatment approaches for CLL.

More Research Needed

The meta-analysis had notable limitations.¹ According to the authors, the substantial heterogeneity among the 21 included studies made direct comparisons challenging, as there were variations in treatment regimens and combination therapies. Additionally, incomplete reporting of survival outcomes restricted the assessment of long-term efficacy, with only progression-free and overall survival metrics available in several cases.

“Future research is recommended to validate these findings and strengthen the results by achieving greater statistical robustness,” the authors said.

References

1. Karimi MA, Norooziseyedhosseini H, Khademi R, et al. Real world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: a meta-analysis of clinical studies. BMC Pharmacol Toxicol. 2025;26(1):43. doi:10.1186/s40360-024-00832-9

2. Chronic lymphocytic leukemia. Mayo Clinic. Updated December 20, 2024. Accessed March 4, 2025. https://www.mayoclinic.org/diseases-conditions/chronic-lymphocytic-leukemia/symptoms-causes/syc-20352428

3. Klein HE. Personalized CLL therapy with MRD guidance improves survival outcomes. AJMC^®. February 6, 2025. Accessed March 4, 2025. https://www.ajmc.com/view/personalized-cll-therapy-with-mrd-guidance-improves-survival-outcomes